1. Field of Invention
This invention relates to substituted indole, benzofuran and benzothiophene derivatives, processes for their preparation, pharmaceutical compositions containing them, and methods of using them as 5-lipoxygenase inhibitors.
2. Background
The leukotrienes are oxidized polyunsaturated fatty acids which posses a multitude of biological activities. They are biosynthesized from arachidonic acid by the enzyme 5-lipoxygenase, which forms an unstable epoxide intermediate leukotriene A.sub.4 (LTA.sub.4). Further enzymatic action on this intermediate gives rise to two general classes of leukotrienes. The first class is represented by leukotriene B.sub.4 (LTB.sub.4). These compounds are chemotactic for inflammatory cells such as polymorphonuclear leukocytes, and cause degranulation and aggregation of inflammatory cells. They also increase vascular permeability, which leads to edema formation. A second class of leukotrienes, LTC.sub.4, LTD.sub.4, and LTE.sub.4, are formed from LTA.sub.4 by the addition of glutathione to the epoxide, and by further metabolic alterations of the peptide portion. These compounds are the major components of slow-reacting substance of anaphylaxis, and have been implicated in immediate hypersensitivity reactions. They can cause, among other effects, the contraction of smooth muscle, increases in mucus secretion, and increased vascular permeability. Many literature reviews are available discussing the biosynthesis and biological activities of the leukotrienes. Examples are
Ford-Hutchinson, ISI Atlas of Science: Pharmacology (1987) 1, 25; Parker, Ann. Rev. Immunol. (1987) 5, 65; Needleman et al., Ann. Rev. Biochem. (1986) 55, 69; Sirois, Advan. Lipid Res. (1985) 21, 79; and Kulkarni and Parale, Drugs of Today (1985) 21, 329.
Because of their many biological effects, the leukotrienes are involved in the pathology of numerous inflammatory diseases (Bray, Agents Actions (1986) 19, 87; and reviews cited above). Such diseases include psoriasis, contact dermatitis, and other skin diseases (Greaves, in Leukotrienes: Their Biological Significance, P. J. Piper, ed; Raven (1986), p 175; Kragballe and Voorhees, Acta Dermato-venereol. (1985) suppl 120, 12), asthma and allergy (Lewis and Robin, J Allergy Clin Immunol. (1985) 76, 259), inflammatory bowel disease, ocular inflammation, arthritis, myocardial ischemia and circulatory shock (Lefer, ISI Atlas of Science: Pharmacology (1988) 2, 109). A therapeutic agent which effectively inhibits the biosynthesis of leukotrienes should be effective in the treatment of these and other inflammatory diseases where leukotrienes play a role (see, for example, Taylor and Clarke, Trends Pharmacol Sci. (1986) 7, 100; and Massicot et al., Prostaglandins (1986) 32, 481) .